Fumonisin B1 induced neural tube defects were not increased in LM/Bc mice fed folate-deficient diet.

SCOPE: Fumonisin B1 (FB1 ) is found in corn-based foods and is a possible risk factor for neural tube defects (NTDs). The mechanism(s) underlying NTD induction by FB1 in LM/Bc mice is not understood; however, evidence suggests disrupted folate transport is involved. METHODS AND RESULTS: Female LM/Bc mice were fed folate-sufficient (control) or folate-deficient diet beginning 5 wk before mating, treated with 0 (vehicle), 2.5 or 10 mg/kg FB1 by intraperitoneal injection on embryonic days 7 (E7) and E8, and their fetuses examined on E16. Dose-dependent NTD induction was found in groups fed the control diet: 3 of 13 low-dose and 10 of 11 high-dose litters were affected. Among groups fed folate-deficient diet, NTDs were found only in 4 of 11 high-dose litters. In another trial, consumption of folate-deficient diet also resulted in fewer NTDs at a dose of 10 mg/kg FB1 and reduced maternal red blood cell folate levels by 80%. In utero death did not fully account for the differences in NTD rates. CONCLUSION: Folate deficiency does not exacerbate NTD induction by FB1 in LM/Bc mice. Interactions between folate, other nutritional factors, and FB1 in this mouse model for NTDs are complex and require further investigation.

Extrusion cooking with glucose supplementation of fumonisin-contaminated corn grits protects against nephrotoxicity and disrupted sphingolipid metabolism in rats.

SCOPE: Fumonisin B1 (FB1) is a mycotoxin found in maize and maize-based foods. It causes animal diseases and is a suspected risk factor for cancer and birth defects in humans. Extrusion cooking reduces FB1 concentrations in maize however toxicity caused by unknown degradation or FB1-matrix reaction products might persist. METHODS AND RESULTS: To test the efficacy of extrusion to reduce FB1 toxicity, Fusarium verticillioides fermented corn (= maize) grits (Batch-1= 9.7 ppm FB1; Batch-2= 50 ppm FB1) were extruded without (Batch-1E; Batch-2E) or with 10% glucose supplementation (Batch-1EG; Batch-2EG). FB1 concentrations were reduced 64% (Batch-2E) to 94% (Batch-1EG) after cooking. When the uncooked and processed grits were fed (50% w/w in rodent chow) to rats for up to 8 weeks, FB1 intakes averaged 354, 103, and 25.1 çg/kg body weight/day for Batch-1, Batch-1E and Batch-1EG and 1804, 698, and 222 çg/kg body weight/day for the Batch-2, Batch-2E and Batch-2EG, respectively. Nephrotoxicity including apoptotic lesions and elevated sphingoid base concentrations decreased in a dose-dependent manner in groups fed Batch-1, Batch-1E, Batch-2, Batch-2E, or Batch-2EG and was absent in the Batch-1EG group. CONCLUSION: Extrusion cooking, especially with glucose supplementation, is potentially useful to reduce FB1 concentrations and toxicity of FB1-contaminated maize.

Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model.

BACKGROUND: Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn worldwide. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. A relationship between maternal ingestion of FB1-contaminated corn during early pregnancy and increased risk for neural tube defects (NTDs) has recently been proposed in human populations around the world where corn is a dietary staple. The current studies provide an in vivo mouse model of FB1 teratogenicity. METHODS: Pregnant LM/Bc mice were injected with increasing doses of FB1 on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and (3)H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GPI-anchored folate receptor (Folbp1) and its association with the lipid raft component, ganglioside GM1, were characterized. Rescue experiments were performed with maternal folate supplementation or administration of gangliosides. RESULTS: Maternal FB1 administration (20 mg/kg of body weight) during early gestation resulted in 79% NTDs in exposed fetuses. Sphingolipid profiles were significantly altered in maternal and embryonic tissues following exposure, and (3)H-folate levels and immunohistochemical expression of Folbp1 were reduced. Maternal folate supplementation partially rescued the NTD phenotype, whereas GM1 significantly restored folate concentrations and afforded almost complete protection against FB1-induced NTDs. CONCLUSIONS: Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize.

Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.

Effect of baking and frying on the in vivo toxicity to rats of cornmeal containing fumonisins.

Fumonisins are mycotoxins produced by Fusarium verticillioides (=F. moniliforme) and other Fusarium species. They are found in corn and corn-based foods. Cooking decreases fumonisin concentrations in food products under some conditions; however, little is known about how cooking effects biological activity. Baked cornbread, pan-fried corncakes, and deep-fried fritters were made from cornmeal that was spiked with 5% w/w F. verticillioides culture material (CM). The cooked materials and the uncooked CM-spiked cornmeal were fed to male rats (n = 5/group) for 2 weeks at high (20% w/w spiked cornmeal equivalents) or low (2% w/w spiked cornmeal equivalents) doses. A control group was fed a diet containing 20% w/w unspiked cornmeal. Toxic response to the uncooked CM-spiked cornmeal and the cooked products included decreased body weight gain (high-dose only), decreased kidney weight, and microscopic kidney and liver lesions of the type caused by fumonisins. Fumonisin concentration, as determined by HPLC analysis, in the 20% w/w pan-fried corncake diet [92.2 ppm of fumonisin B(1) (FB(1))] was slightly, but not statistically significantly, lower than those of the 20% w/w baked cornbread (132.2 ppm of FB(1)), deep-fried fritter (120.2 ppm of FB(1)) and CM-spiked cornmeal (130.5 of ppm FB(1)) diets. Therefore, baking and frying had no significant effect on the biological activity or concentration of fumonisins in these corn-based products, and the results provided no evidence for the formation of novel toxins or "hidden" fumonisins during cooking.